Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death world-wide. HCC has well characterized risk factors: chronic HBV or HCV infection accounts for over 85% of all HCC cases. Such well- defined population makes HCC an ideal type of malignancy for chemoprevention. Recently, we established novel murine HCC models by overexpressing c-Myc or concomitant expressing activated forms of AKT and Ras (AKT/Ras) in mice. We found that HCCs induced by c-Myc as well as AKT/Ras both demonstrated increased lipogenesis. However, detailed lipid profiling analysis showed that while HCC induced by AKT/Ras has high levels of triglyceride and moderately elevated cholesterol, HCC induced by c-Myc shows extremely high levels of cholesterol, but mild increase in triglyceride levels. Based on these preliminary results, we hypothesize that different oncogenes induce distinct lipid metabolic pathways during hepatic carcinogenesis; and drugs that target distinct lipogenic pathways may show drastically different chemoprevention activities in liver tumors induced by specific oncogenes. The hypothesis will be tested in two aims. In Aim One, we will determine the chemoprevention activity of lipogenic pathway inhibitors including C-75 (FASN inhibitor), simvastatin (MHGCR inhibitor) and Fatostatin (SREBP1/2 inhibitor) in c-Myc induced mouse HCC. In Aim Two, we will determine the chemoprevention activity of lipogenic pathway inhibitors in AKT/Ras induced mouse HCC. Altogether, the proposed study will examine the chemoprevention potential of lipogenic pathway inhibitors that target distinct lipogenic pathway components in the context of different oncogenes. It represents an innovative pilot project with defined research goal and scope. The study will provide novel insight into the role of lipid metabolism during hepatic carcinogenesis, and provide novel strategy for the prevention of this malignancy. PUBLIC HEALTH RELEVANCE: Liver cancer is a deadly disease, lacking any effective treatment options. The proposal seeks to determine the chemoprevention activity of specific compounds involving lipid metabolism in preventing liver cancer development in mouse models. The study is likely to provide novel strategy for the prevention of this malignancy.